rs555848272

chr5-141584111-TC-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005219.5(DIAPH1):c.402+12del variant causes a intron change. The variant allele was found at a frequency of 0.00482 in 1,554,796 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (35 hom.)
• Consequence: DIAPH1 NM_005219.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 3.59

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 5-141584111-TC-T is Benign according to our data. Variant chr5-141584111-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163077.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00377 (574/152188) while in subpopulation AMR AF= 0.0109 (167/15278). AF 95% confidence interval is 0.00958. There are 5 homozygotes in gnomad4. There are 277 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.402+12del		intron_variant		ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.402+12del		intron_variant		5	NM_005219.5	A2

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152076 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00375 AC: 929 AN: 247676 Hom.: 10 AF XY: 0.00364 AC XY: 488 AN XY: 134236

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00757

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000431

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00529

Gnomad OTH exome AF: 0.00532

GnomAD4 exome AF: 0.00494 AC: 6923 AN: 1402608 Hom.: 35 Cov.: 25 AF XY: 0.00481 AC XY: 3371 AN XY: 700776

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00828

Gnomad4 ASJ exome AF: 0.000233

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000472

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00584

Gnomad4 OTH exome AF: 0.00447

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152188 Hom.: 5 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74418

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00404 Hom.: 1

Bravo AF: 0.00438

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 01, 2014	402+12delG in intron 4 of DIAPH1: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 1% (74/7878) of European American chromosomes and in 0.25 % (9/3678) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nonsyndromic Hearing Loss, Mixed Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

DIAPH1: BS2 -

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs555848272; hg19: chr5-140963678;